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Peiyan Yuan Xin Mao Xiaofeng Wu Si Si Liew Lin Li Shao Q. Yao 《Angewandte Chemie (International ed. in English)》2019,58(23):7657-7661
Mitochondria are key organelles in mammalian cells whose dysfunction is linked to various diseases. Drugs targeting mitochondrial proteins provide a highly promising strategy for potential therapeutics. Methods for the delivery of small‐molecule drugs to the mitochondria are available, but these are not suitable for macromolecules, such as proteins. Herein, we report the delivery of native proteins and antibodies to the mitochondria using biodegradable silica nanoparticles (BS–NPs). The modification of the nanoparticle surface with triphenylphosphonium (TPP) and cell‐penetrating poly(disulfide)s (CPD) facilitated their rapid intracellular uptake with minimal endolysosomal trapping, providing sufficient time for effective mitochondrial localization followed by glutathione‐triggered biodegradation and of native, functional proteins into the mitochondria. 相似文献
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《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(41):12655-12659
Antibodies are important biopharmaceuticals, but almost all existing antibody‐based drugs are limited to targeting antigens located at the cell exterior because of the inability of antibodies to enter the cell interior. Available methods for intracellular delivery of antibodies have major shortcomings. Herein, we report an approach to encapsulate native antibodies in a biodegradable silica nanoquencher (BS‐qNP), which could undergo efficient cellular uptake and intracellular degradation to release antibodies only under hypoxic conditions. By coating the surface of BS‐qNP with cell‐penetrating poly(disulfide)s (CPD), the delivered antibodies (or other proteins) avoided endolysosomal trapping. Doping of the silica coating with a fluorescent dye and a dark hole quencher further endowed BS‐qNP with hypoxia‐responsive fluorescence turn‐on property. Our antibody delivery system thus provides the first platform capable of stable encapsulation, efficient uptake, on‐demand antibody release, and imaging of release/cell state. 相似文献
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Justin T. Huckaby Christina L. Parker Tim M. Jacobs Alison Schaefer Daniel Wadsworth Alexander Nguyen Anting Wang Jay Newby Samuel K. Lai 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(17):5660-5664
Mucus represents a major barrier to sustained and targeted drug delivery to mucosal epithelium. Ideal drug carriers should not only rapidly diffuse across mucus, but also bind the epithelium. Unfortunately, ligand‐conjugated particles often exhibit poor penetration across mucus. In this work, we explored a two‐step “pretargeting” approach through engineering a bispecific antibody that binds both cell‐surface ICAM‐1 and polyethylene glycol (PEG) on the surface of nanoparticles, thereby effectively decoupling cell targeting from particle design and formulation. When tested in a mucus‐coated Caco‐2 culture model that mimics the physiological process of mucus clearance, pretargeting increased the amount of PEGylated particles binding to cells by around 2‐fold or more compared to either non‐targeted or actively targeted PEGylated particles. Pretargeting also markedly enhanced particle retention in mouse intestinal tissues. Our work underscores pretargeting as a promising strategy to improve the delivery of therapeutics to mucosal surfaces. 相似文献
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《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2018,130(6):1548-1552
Intracellular delivery of therapeutic proteins is highly challenging and in most cases requires chemical or genetic modifications. Herein, two complementary approaches for endocytosis‐independent delivery of proteins to live mammalian cells are reported. By using either a “glycan” tag naturally derived from glycosylated proteins or a “traceless” tag that could reversibly label native lysines on non‐glycosylated proteins, followed by bioorthogonal conjugation with cell‐penetrating poly(disulfide)s (CPDs), we achieved intracellular delivery of proteins (including antibodies and enzymes) which, upon spontaneous degradation of CPDs, led to successful release of their “native” functional forms with immediate bioavailability. 相似文献
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Ying Wang Jintang Du Huafei Zou Yan Liu Yuhan Zhang Jose Gonzalez Elizabeth Chao Lucy Lu Pengyu Yang Holly Parker Van Nguyen‐Tran Weijun Shen Danling Wang Peter G. Schultz Feng Wang 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2016,128(40):12663-12666
Glucagon‐like peptide‐1 (GLP‐1) receptor (GLP‐1R), glucagon (GCG) receptor (GCGR), and glucose‐dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) receptor (GIPR), are three metabolically related peptide hormone receptors. A novel approach to the generation of multifunctional antibody agonists that activate these receptors has been developed. Native or engineered peptide agonists for GLP‐1R, GCGR, and GIPR were fused to the N‐terminus of the heavy chain or light chain of an antibody, either alone or in pairwise combinations. The fusion proteins have similar in vitro biological activities on the cognate receptors as the corresponding peptides, but circa 100‐fold longer plasma half‐lives. The GLP‐1R mono agonist and GLP‐1R/GCGR dual agonist antibodies both exhibit potent effects on glucose control and body weight reduction in mice, with the dual agonist antibody showing enhanced activity in the latter. 相似文献
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